Herpes simplex virus type 1 (HSV-1) is a complex DNA virus that causes life long infection in the majority of the world's population. In most people the disease is characterized by a primary illness that includes a sore throat and is variably followed by many years of asymptomatic carriage punctuated by occasional local reactions, usually occurring as "fever blisters." The virus is carried in its latent phase in neurons and may cause encephalitis. Newborn babies, on the other hand, present with a much different clinical picture that is characterized by either localized disease, encephalitis, or disseminated infection with a high mortality. Recent work in our laboratory has demonstrated that HSV induces the production of inflammatory cytokines through its interaction with TLR2. The same viruses also induce the production of interferon through TLR9. The mechanism by which HSV stimulates TLRs will be investigated using viral genetics and expression of isolated proteins. Using transfected cells and knockout mice we plan to define the pathways responsible for HSV induced cytokines and interferon and determine how TLRs affect both the immune response to HSV (using animal models), and the development of reactivation disease (in humans).